Regular use of non-steroidal anti-inflammatory drugs (NSAIDs) including selective COX-2 inhibitors reduces the risk of prostate cancer. However, significant gastro-intestinal and renal toxicity, and increased risk of cardiovascular events associated with long-term use of COX-2 inhibitors undermine the use of these drugs as chemopreventive agents. Herbal remedies with anti-inflammatory and antioxidant activity without serious side effects provide an attractive alternative to these pharmaceuticals for prevention of prostate cancer. Oleanolic acid and ursolic acid are naturally occurring triterpenoids that have been used in traditional medicine as antibacterial, anti-inflammatory, and anti-cancer agents. Recent studies have shown that synthetic oleanane triterpenoids: 2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acid (CDDO) and its C-28 methyl ester (CDDO- Me) and C-28 imidazole (CDDO-Im) are potent anti-inflammatory agents. Our preliminary data demonstrate that synthetic triterpenoids strongly inhibit cell proliferation and induce apoptosis in prostate cancer cell lines in potency order of CDDO-Me>CDDO-Im>CDDO. Furthermore, CDDO-Me inhibits the expression of antiapoptotic Akt and Akt-regulated NF-:B and p-mTOR pro-survival signaling molecules and growth of tumor xenografts in vivo. We hypothesize that early intervention with CDDO-Me will prevent or delay the development of prostate cancer in transgenic adenocarcinoma of the mouse prostate (TRAMP) model and growth of orthotopic tumor xenografts in nude mice by inhibiting Akt, NF-:B and mTOR, and cellular processes regulated by these molecules (e.g., cell proliferation, apoptosis, inflammation, angiogenesis and metastasis). We will test this hypothesis by performing four specific aims. Specific Aim 1 will test the hypothesis that early intervention with CDDO-Me will prevent the development and/or retard the progression of prostate cancer in TRAMP mice. Specific Aim 2 will test that prevention of prostate tumorigenesis by CDDO-Me is linked to the inhibition of Akt/NF-:B and Akt/mTOR signaling pathways and cellular processes (cell proliferation, apoptosis, inflammation, metastasis, and angiogenesis) regulated by these molecular targets. Specific Aim 3 will determine the mechanism by which CDDO-Me inhibits Akt, and Specific Aim 4 will determine the efficacy and the mechanism by which CDDO-Me inhibits the growth of prostate tumor in an orthotopic xenograft model. This study will provide critical preclinical information on the efficacy and mechanism of action of CDDO-Me as a safe chemopreventive/therapeutic agent for prostate cancer in man. PUBLIC HELATH RELEVANCE Because the development of prostate cancer progresses slowly over a long period of time, early intervention with non-toxic herbal compounds to prevent or slow down the progression of prostate cancer is a promising approach to conquer this disease. Our proposal to investigate the efficacy and the mechanism of action of CDDO-Me, a synthetic triterpenoid derived from naturally occurring oleanolic acid, in prevention of prostate cancer in TRAMP mouse and tumor xenograft models will provide critical information for clinical trials of CDDO-Me to prevent prostate cancer in man.